DESC:[001] FIELD OF THE INVENTION

[002] The present invention relates to the pharmaceutical composition comprising 24-nor-ursodeoxycholic acid (nor-UDCA) or pharmaceutically acceptable salt or ester thereof and the process for preparation thereof. The present invention more specifically relates to the stable sterile injectable pharmaceutical composition comprising nor-UDCA or pharmaceutically acceptable salt or ester thereof and at least one solubilizer/solubilizing agent or combinations thereof. This sterile injectable pharmaceutical composition provides sufficient solubilization of nor-UDCA that results in improved shelf-life of the product and reduced likelihood of precipitation during the injection into the vein by intravenous administration. The invention also relates to methods for treatment of inflammatory cholestatic liver disease.

[003] BACKGROUND OF THE INVENTION

[004] 24-nor-ursodeoxycholic acid (nor-UDCA) is an ursodeoxycholic analog (bile acid derivative) used for the treatment and/or the prevention of liver diseases, preferably chronic liver diseases. Nor-UDCA has the following structural formula

[005] EP Patent No. 0624595B1 (“EP ‘595 Patent”) discloses nor-UDCA, its method for preparation and its use especially to lower cholesterol at a daily dose depending on body weight and constitution of the patient in the range of 3 mg to 5000 mg, preferably in the dose range 10 to 1000 mg. Further EP ‘595 Patent discloses various dosage forms, preferably oral dosage forms in the form of tablets, capsules or liquids.

[006] US Patent No. 8,951,995 (“US ‘995 Patent”) discloses a method of treating an inflammatory cholestatic liver disease in a subject by administering the subject a pharmaceutical composition comprising nor-UDCA and/or pharmaceutically acceptable salt or ester thereof; wherein the inflammatory cholestatic liver disease is primary sclerosing cholangitis (PSC), primary biliary cirrhosis (PBC) or progressive familial intrahepatic cholestasis, in particular progressive familial intrahepatic cholestasis type 1, 2 and 3, cystic fibrosis, drug-induced cholestasis or a noncholestatic liver disease such as chronic viral hepatitis (B,C,D), alcoholic and non-alcoholic steatohepatitis, autoimmune hepatitis, hemochromatosis, Wilson disease and alpha-1-antitrypsin deficiency. Further US ‘995 Patent discloses injectable preparations, for example sterile injectable aqueous or oleaginous suspensions, that can be formulated according to known art using suitable dispersing agents, wetting agents and/or suspending agents and the sterile injectable preparation can also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, wherein the acceptable vehicle solvents that can be used are water and isotonic sodium chloride solution and further sterile fixed oils are also conventionally used as a solvent or suspending medium. The suitable vehicles for parenteral application as disclosed in US ‘995 Patent consist of solutions, preferably oily or aqueous solutions, as well as suspensions, emulsions or implants.

[007] US Patent No. 9,512,167 discloses chemically pure polymorph of nor-UDCA or of a pharmaceutically acceptable salt or esters thereof, wherein the total amount of chemical impurities is less than 0.5%, at least 60% of the polymorph particles have a size <10 µm, and wherein said polymorph contains substantially no detectable amorphous nor-UDCA. Further US ‘167 Patent discloses that the pharmaceutical composition of this invention may be formulated for oral, parenteral, subcutaneous, intravenous, intramuscular, nasal, inhalative, topical or rectal administration and usually comprise one or more pharmaceutically acceptable excipients.

[008] The above prior-arts discloses the pharmaceutical compositions for parenteral administration that are in the form of solutions (oily or aqueous), suspensions, emulsions or implants. The sterile injectable solutions discussed in above prior arts disclose that the nor-UDCA is dissolved in a parenterally acceptable diluent or solvent, wherein the solvent is water and isotonic sodium chloride. The present inventors have found that nor-UDCA or its pharmaceutically acceptable salts or esters thereof have low intrinsic solubility and it is difficult to formulate in a water-based parenteral formulation that is sufficiently concentrated and stable and present in a medium having a physiologically acceptable pH.

[009] In view of the above disadvantages of low intrinsic solubility of nor-UDCA and its difficulty in formulating the water-based parenteral formulation, there exists a need to formulate a stable injectable pharmaceutical composition, preferably injectable solution for intravenous administration comprising nor-UDCA or pharmaceutically acceptable salts or esters thereof.

[010] SUMMARY OF THE INVENTION

[011] The present invention relates to a pharmaceutical composition preferably stable injectable solution comprising 24-nor-ursodeoxycholic acid (nor-UDCA) or pharmaceutically acceptable salt or ester thereof.

[012] In embodiments of the invention, the present invention provides a sterile injectable dosage form comprising 24-nor-ursodeoxycholic acid (nor-UDCA) or pharmaceutically acceptable salt or ester thereof and at least one pharmaceutically acceptable excipient.

[013] In embodiments of the invention, the present invention provides a sterile injectable composition comprising nor-UDCA and a solubilizing agent.

[014] In a specific embodiment, the present invention provides a sterile injectable composition comprising
(a) Nor-UDCA and
(b) a solubilizing agent selected from group consisting of cyclodextrins and its derivatives, N-methyl-2-pyrrolidone (NMP), 1,3-dimethyl-2-imidazolidinone, dimethyl acetamide, dimethyl sulfoxide (DMSO), acetone, tetrahydrofuran (THF), 1,4-dioxane, acetonitrile, dimethyl formamide (DMF), propylene carbonate, ethanol, benzyl alcohol, isopropyl alcohol, ethylene glycol, propylene glycol, butylene glycol, glycerol, polysorbates, polyalkylene glycols (polyethylene glycol, polypropylene glycol and polybutylene glycol), polyoxyethylene esters of 12-hydroxystearic acid (polyethylene glycol 660 hydroxystearate; Solutol® HS 15), Polyoxyl-35 castor oil (Cremophor EL), polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus®), soya bean oil and egg lecithin or combinations thereof.

[015] In a more specific embodiment of the invention, the invention is directed to a pharmaceutical composition for intravenous administration comprising
(a) nor-UDCA and
(b) a solubilizing agent selected from the group consisting of modified cyclodextrins, isopropyl alcohol and dimethyl sulfoxide (DMSO).

[016] In a specific embodiment of the invention, the invention is directed to a pharmaceutical composition for intravenous administration comprising
(a) nor-UDCA and
(b) a modified cyclodextrin.

[017] In a further specific embodiment of the invention, the modified cyclodextrin is sulfobutylether-ß-cyclodextrin.

[018] In further embodiments, the composition shall comprise a buffering agent.

[019] In further embodiment, said pharmaceutical composition for intravenous administration comprise the components and quantities each as follows:
Components Quantity
nor-UDCA 1 mg/mL to about 100 mg/mL
sulfobutylether-ß-cyclodextrin. 5 mg/mL to about 300 mg/mL
Water for Injection q.s to 1 mL

[020] DETAILED DESCRIPTION OF THE INVENTION

[021] The present invention provides a stable injectable composition comprising nor-UDCA or its pharmaceutically acceptable salts or esters thereof.

[022] In embodiments of the invention, the present invention provides a sterile injectable composition comprising about 1 mg/mL to about 100 mg/mL nor-UDCA, more preferably about 15 mg/mL to about 40 mg/mL of nor-UDCA and most preferably of about 20 mg/mL of nor-UDCA.

[023] The present invention further provides a sterile injectable composition comprising nor-UDCA or its pharmaceutically acceptable salts or esters thereof and a solubilizing agent.

[024] As used herein, the term “solubilizing agent” is intended to mean a compound used to assist and or increase the solubility of a compound (nor-UDCA or its pharmaceutically acceptable salts or esters thereof) going into solution.

[025] The solubilizing agents used in the present invention are selected from the group consisting of cyclodextrins or its derivatives (cyclodextrin derivatives are often referred to as modified cyclodextrins), polar aprotic solvents, non-aqueous polar protic solvents, polyoxyethylene esters of 12-hydroxystearic acid (polyethylene glycol 660 hydroxystearate; Solutol® HS 15), Polyoxyl-35 castor oil (Cremophor EL), polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus®), soya bean oil and egg lecithin or combinations thereof.

[026] In embodiments of the invention, the present injectable solution compositions of nor-UDCA comprising the solubilizing agent cyclodextrin or its derivates selected from group consisting of a-cyclodextrin; ß-cyclodextrin; ?-cyclodextrin; cyclodextrin derivatives such as ether and mixed ether derivatives and those derivatives bearing sugar residues such as hydroxyethyl, hydroxypropyl (including 2- and 3-hydroxypropyl) and dihydroxypropyl ethers, their corresponding mixed ethers and further mixed ethers with methyl or ethyl groups, such as methyl-hydroxyethyl, ethyl-hydroxyethyl and ethyl-hydroxypropyl ethers of a-, ß- and ?-cyclodextrin; maltosyl, glucosyl and maltotriosyl derivatives of ß- and ?-cyclodextrin, which may contain one or more sugar residues, e.g. glucosyl or diglucosyl, maltosyl or dimaltosyl, as well as various mixtures thereof, e.g. a mixture of maltosyl and dimaltosyl derivatives; cyclodextrin derivatives comprising anionic functional groups such as sulfobutylether derivatives, sulfonates, phosphates, and the like, such as hydroxypropyl-ß-cyclodextrin, hydroxypropyl-?-cyclodextrin, sulfobutylether-ß-cyclodextrin, and sulfobutylether-?-cyclodextrin, as well as hydroxyethyl-ß-cyclodextrin, hydroxyethyl-?-cyclodextrin, dihydroxypropyl-ß-cyclodextrin, glucosyl-ß-cyclodextrin, diglucosyl-ß-cyclodextrin, maltosyl-ß-cyclodextrin, maltosyl-?-cyclodextrin, maltotriosyl-ß-cyclodextrin, maltotriosyl-?-cyclodextrin and dimaltosyl-ß-cyclodextrin. The most preferably used cyclodextrin or its derivatives used in the present invention is sulfobutylether-ß-cyclodextrin.

[027] In embodiments of the invention, the present injectable solution compositions of nor-UDCA comprising the solubilizing agent polar aprotic solvents selected from group consisting of N-methyl-2-pyrrolidone (NMP), 1,3-dimethyl-2-imidazolidinone, dimethyl acetamide, dimethyl sulfoxide (DMSO), acetone, tetrahydrofuran (THF), 1,4-dioxane, acetonitrile, dimethyl formamide (DMF) and propylene carbonate.

[028] In embodiments of the invention, the present injectable solution compositions of nor-UDCA comprising the solubilizing agent non-aqueous polar protic solvents selected from the group consisting of alkyl alcohols (for example, ethanol and benzyl alcohol), ethylene glycol, propylene glycol, butylene glycol, glycerol, polysorbates (for example Tween 20, Tween 40 and Tween 80) and polyalkylene glycols (polyethylene glycol, polypropylene glycol and polybutylene glycol).

[029] In an embodiment of the invention, the present invention relates to a sterile injectable composition comprising
(a) nor-UDCA and
(b) solubilizing agent,
in a ratio of 0.1:1 to 1:0.1.

[030] In a specific embodiment of the invention, the present invention relates to a sterile injectable composition comprising
(a) nor-UDCA and
(b) a solubilizing agent selected from group consisting of cyclodextrins and its derivatives, N-methyl-2-pyrrolidone (NMP), 1,3-dimethyl-2-imidazolidinone, dimethyl acetamide, dimethyl sulfoxide (DMSO), acetone, tetrahydrofuran (THF), 1,4-dioxane, acetonitrile, dimethyl formamide (DMF), propylene carbonate, ethanol, benzyl alcohol, ethylene glycol, propylene glycol, butylene glycol, glycerol, polysorbates, polyalkylene glycols (polyethylene glycol, polypropylene glycol and polybutylene glycol), polyoxyethylene esters of 12-hydroxystearic acid (polyethylene glycol 660 hydroxystearate; Solutol® HS 15), Polyoxyl-35 castor oil (Cremophor EL), polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus®), soya bean oil and egg lecithin or combinations thereof.

[031] Table 1 shows the impact of various solubilizing agents, solvents, buffers and surfactants on the solubility of nor-UDCA. The surfactants like sodium lauryl sulfate and polysorbate 80 and sodium lauryl sulfate did not enhance the solubility of nor-UDCA. Further the buffers like acetate buffer, phosphate buffer at various pH and also the combination of buffers with surfactants like sodium lauryl sulfate did not enhance the solubility of nor-UDCA. The solvents like acetonitrile, methanol, acetic acid, ethanol did not enhance the solubility of nor – UDCA. The solubility of nor-UDCA is enhanced with isopropyl alcohol, DMSO and sulfobutylether-ß-cyclodextrin.
Table – 1:
S.No Solvents / Buffer media Solubility of Nor-UDCA
mg/mL
1. Sodium lauryl sulphate 0.5% 0.1300
2. Sodium lauryl sulphate 1.0% 0.0800
3. Sodium lauryl sulphate 1.5% 0.1300
4. Polysorbate-80 - 0.5% 0.0000
5. Polysorbate-80 - 1.0% 0.0000
6. Polysorbate-80 - 1.5% 0.0000
7. Acetonitrile 0.0300
8. Methanol 0.7213
9. Acetic acid 0.6506
10. Ethanol 0.5990
11. pH 1.2 - 0.1 N HCl 0.0000
12. pH 4.5 Acetate buffer 0.0000
13. pH 6.8 Phosphate buffer 0.0000
14. pH 7.2 Phosphate buffer 0.0000
15. Water 0.0000
16. 0.1% HCl + Sodium lauryl sulphate 0.5% 0.0304
17. 0.1% HCl + Sodium lauryl sulphate 1.0% 0.0639
18. 0.1% HCl + Sodium lauryl sulphate 1.5% 0.0911
19. 0.1% HCl + 0.5% Polysorbate – 80. 0.0000
20. 0.1% HCl + 1.0% Polysorbate – 80. 0.0000
21. 0.1% HCl + 1.5% Polysorbate – 80. 0.0000
22. pH 4.5 + 0.5% sodium lauryl sulphate 0.0332
23. pH 4.5 + 0.5% sodium lauryl sulphate 0.0766
24. pH 4.5 + 0.5% sodium lauryl sulphate 0.1087
25. pH 4.5 + 0.5% Polysorbate – 80. 0.0091
26. pH 4.5 + 1.0% Polysorbate – 80. 0.0120
27. pH 4.5 + 1.5% Polysorbate – 80. 0.0081
28. pH 6.8 + 0.5% Sodium lauryl sulphate 0.0220
29. pH 6.8 + 0.5% Sodium lauryl sulphate 0.0243
30. pH 6.8 + 0.5% Sodium lauryl sulphate 0.0237
31. pH 6.8 + 0.5% Polysorbate – 80. 0.0366
32. pH 6.8 + 1.0% Polysorbate – 80. 0.0381
33. pH 6.8 + 1.5% Polysorbate – 80. 0.0454
34. pH 8.4 Phosphate buffer + 2% Sodium lauryl sulphate 0.2500
35. pH 8.4 Phosphate buffer 0.1970
36. Water 0.0000
37. Water + 1.0% Sodium lauryl sulphate 0.0840
38. Water + 1.5% Sodium lauryl sulphate 0.1330
39. Water + 2.0% Sodium lauryl sulphate 0.1710
40. pH 8.0 Phosphate buffer 0.1600
41. pH 8.0 Phosphate buffer + 20% Isopropyl alcohol 0.3770
42. pH 8.0 Phosphate buffer + 30% Isopropyl alcohol 0.7270
43. pH 8.0 Phosphate buffer + 40% Isopropyl alcohol 0.5490
44. Isopropyl alcohol 0.9380
45. Dibasic sodium phosphate + pH 6.8 + 0.1% Polysorbate 80 0.0000
46. Dibasic sodium phosphate + pH 8.2 + 0.1% Polysorbate 80 0.0535
47. pH 8.4 Sodium phosphate buffer 0.1857
48. pH 8.4 Sodium phosphate buffer + 0.5% Polysorbate 80. 0.1944
49. pH 8.4 Sodium phosphate buffer + 1.0% Polysorbate 80. 0.2081
50. pH 8.4 Sodium phosphate buffer 1.5% Polysorbate 80 0.2259
51. pH 8.4 Sodium phosphate buffer 2.0% Polysorbate 80 0.2392
52. pH 8.4 Sodium phosphate buffer + 1.0% Sodium lauryl sulphate. 0.3285
53. pH 8.4 Sodium phosphate buffer + 1.5% Sodium lauryl sulphate. 0.3656
54. pH 8.4 Sodium phosphate buffer 2.0% Sodium lauryl sulphate. 0.4260
55. pH 8.0 Sodium phosphate buffer 0.1796
56. pH 8.0 Sodium phosphate buffer + 0.5% Polysorbate 80. 0.1649
57. pH 8.0 Sodium phosphate buffer + 1.0% Polysorbate 80. 0.1797
58. pH 8.0 Sodium phosphate buffer + 1.5% Polysorbate 80. 0.1744
59. pH 8.0 Sodium phosphate buffer + 2.0% Polysorbate 80. 0.1877
60. 10% DMSO + 20% sulfobutylether-ß-cyclodextrin 1.8795
61. DMSO 1.8663
62. 0.9% SALINE 0.0000
63. 1% DMSO + 10% sulfobutylether-ß-cyclodextrin 1.0340
64. 5% sulfobutylether-ß-cyclodextrin 1.9882
65. 4% sulfobutylether-ß-cyclodextrin 2.0243
66. pH 4.5 Acetate buffer + 4% Beta-Cyclodextrin 2.0119

[032] In a more specific embodiment of the invention, the invention is directed to a pharmaceutical composition for intravenous administration comprising
(a) nor-UDCA and
(b) a solubilizing agent selected from the group consisting of modified cyclodextrins, isopropyl alcohol and dimethyl sulfoxide (DMSO).

[033] In a specific embodiment of the invention, the invention is directed to a pharmaceutical composition for intravenous administration comprising
(a) nor-UDCA and
(b) a modified cyclodextrin.

[034] In a further specific embodiment of the invention, the modified cyclodextrin is sulfobutylether-ß-cyclodextrin.

[035] In a further embodiment of the invention, the present invention relates to a sterile injectable composition comprising
(a) nor-UDCA and
(b) sulfobutylether-ß-cyclodextrin.

[036] In specific embodiments of the invention, the present invention relates to a sterile injectable composition comprising about 5 mg/mL to about 300 mg/mL of sulfobutylether-ß-cyclodextrin, more preferably about 150 mg/mL to about 250 mg/mL of sulfobutylether-ß-cyclodextrin.

[037] In embodiments of the invention the present invention relates to sterile injectable composition comprising
(a) about 10 mg/mL to about 100 mg/mL nor-UDCA and
(b) about 5 mg/mL to about 300 mg/mL of sulfobutylether-ß-cyclodextrin.

[038] In further embodiment of the invention, the present injectable pharmaceutical compositions optionally further comprise pH adjusting agents. The pH adjusting agents used in the present invention is selected from group consisting of sodium hydroxide and hydrochloric acid. The pH of the injectable composition of the present invention is of about 2.0 to about 8.0.

[039] In another embodiment, the present invention provides an injectable pharmaceutical composition comprising
(a) nor-UDCA
(b) sulfobutylether-ß-cyclodextrin,
(c) water and
(d) optionally a pH adjusting agent or a buffering agent.

[040] In another embodiment, the present invention provides an injectable pharmaceutical composition comprising
(a) nor-UDCA
(b) sulfobutylether-ß-cyclodextrin,
(c) water and
(d) optionally a pH adjusting agent.

[041] In embodiments of the invention, the present invention may further comprise preservative, antioxidant/chelating agent or both, buffering agent and tonicity modifier.

[042] As used herein, the term “preservative” is intended to mean a compound used to prevent the growth of microorganisms. Such compounds include, by way of example and without limitation, benzalkonium chloride, benzethonium chloride, benzoic acid, benzyl alcohol, cetylpyridinium chloride, chlorobutanol, phenol, phenylethyl alcohol, phenylmercuric nitrate, phenylmercuric acetate, thimerosal, metacresol, myristylgamma picolinium chloride, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, sorbic acid, thymol, and methyl, ethyl, propyl, or butyl parabens and others known to those of ordinary skill in the art.

[043] As used herein, the term “antioxidant” is intended to mean an agent which inhibits oxidation and thus is used to prevent the deterioration of preparations by the oxidative process. Such compounds include by way of example and without limitation, acetone, sodium bisulfate, ascorbic acid, ascorbyl palmitate, citric acid, butylated hydroxyanisole, butylated hydroxytoluene, hydrophosphorous acid, monothioglycerol, propyl gallate, sodium ascorbate, sodium citrate, sodium sulfide, sodium sulfite, sodium bisulfite, sodium formaldehyde sulfoxylate, thioglycolic acid, sodium metabisulfite, EDTA (edetate), pentetate and others known to those of ordinary skill in the art.

[044] As used herein, the term “buffering agent” is intended to mean a compound used to resist change in pH upon dilution or addition of acid or alkali. Such compounds include, by way of example and without limitation, acetic acid, sodium acetate, adipic acid, benzoic acid, sodium benzoate, citric acid, maleic acid, monobasic sodium phosphate, dibasic sodium phosphate, lactic acid, tartaric acid, glycine, potassium metaphosphate, potassium phosphate, monobasic sodium acetate, sodium bicarbonate, sodium tartrate and sodium citrate anhydrous and dihydrate and others known to those of ordinary skill in the art.

[045] As used herein, the term “tonicity modifier” is intended to mean a compound or compounds that can be used to adjust the tonicity of the liquid formulation. Suitable tonicity modifiers include glycerin, lactose, mannitol, dextrose, sodium chloride, sodium sulfate, sorbitol, trehalose and others known to those or ordinary skill in the art. In one embodiment, the tonicity of the liquid formulation approximates that of the tonicity of blood or plasma.

[046] The formulation of the invention can also include water, glucose or saline and combinations thereof. In particular embodiments, the formulation includes water, saline, and glucose.

[047] In embodiments of the invention, the present invention relates stable injectable compositions comprising nor-UDCA for the treatment of inflammatory cholestatic liver disease in a subject, wherein the inflammatory cholestatic liver disease is primary sclerosing cholangitis (PSC), primary biliary cirrhosis (PBC) or progressive familial intrahepatic cholestasis, in particular progressive familial intrahepatic cholestasis type 1, 2 and 3, cystic fibrosis, drug-induced cholestasis or a noncholestatic liver disease such as chronic viral hepatitis (B,C,D), alcoholic and non-alcoholic steatohepatitis, autoimmune hepatitis, hemochromatosis, Wilson disease and alpha-1-antitrypsin deficiency.

[048] The following examples are provided to illustrate the present invention. It is understood, however, that the invention is not limited to the specific conditions or details described in the example below. The example should not be construed as limiting the invention as the examples merely provide specific methodology useful in the understanding and practice of the invention and its various aspects. While certain preferred and alternative embodiments of the invention have been set forth for purposes of disclosing the invention, modification to the disclosed embodiments can occur to those who are skilled in the art.

[049] Example – 1: Nor-UDCA Injectable Composition

[050] Injectable Composition:
S. No Ingredients Quantity/mL
1 Nor-ursodeoxycholic acid 20 mg
2 Sulfobutylether-ß-cyclodextrin 160 mg
3 Sodium hydroxide Q.s to pH
4 Hydrochloric acid Q.s to pH
5 Water for Injection Q.s to 1 mL

[051] Process for Preparation:
[052] Sulfobutyl ether-ß-cyclodextrin is dissolved in required quantity of water for injection and further Nor-ursodeoxycholic acid is dissolved and the pH is adjusted with sodium hydroxide to form a final solution which is filtered and sterilized by using aseptic filtration and/or by autoclaving.

[053] Comparative Example: 1

[054] Injectable Composition with Sodium Chloride

S. No Ingredients Quantity/mL
1 Nor-ursodeoxycholic acid 5 mg
2 Sodium Chloride 9 mg
3 Water for Injection Q.s to 1 mL

[055] Process for Preparation

[056] Water for Injection was taken in beaker and sodium chloride was added to water for Injection. To the above sodium chloride solution nor-UDCA was added and stirred.

[057] Observation: It was found that nor-UDCA was insoluble in sodium chloride solution.
,CLAIMS:1. A sterile injectable composition comprising
(a) nor-UDCA and
(b) a solubilizing agent selected from group consisting of cyclodextrins and its derivatives, N-methyl-2-pyrrolidone (NMP), 1,3-dimethyl-2-imidazolidinone, dimethyl acetamide, dimethyl sulfoxide (DMSO), acetone, tetrahydrofuran (THF), 1,4-dioxane, acetonitrile, dimethyl formamide (DMF), propylene carbonate, ethanol, isopropyl alcohol, benzyl alcohol, ethylene glycol, propylene glycol, butylene glycol, glycerol, polyalkylene glycols (polyethylene glycol, polypropylene glycol and polybutylene glycol), polyoxyethylene esters of 12-hydroxystearic acid (polyethylene glycol 660 hydroxystearate; Solutol® HS 15), Polyoxyl-35 castor oil (Cremophor EL), polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus®), soya bean oil and egg lecithin or combinations thereof.

2. The sterile injectable composition as claimed in claim 1 wherein cyclodextrin and derivatives are selected from the group consisting of a-cyclodextrin; ß-cyclodextrin; ?-cyclodextrin; cyclodextrin derivatives such as ether and mixed ether derivatives and those derivatives bearing sugar residues such as hydroxyethyl, hydroxypropyl (including 2- and 3-hydroxypropyl) and dihydroxypropyl ethers, their corresponding mixed ethers and further mixed ethers with methyl or ethyl groups, such as methyl-hydroxyethyl, ethyl-hydroxyethyl and ethyl-hydroxypropyl ethers of a-, ß- and ?-cyclodextrin; maltosyl, glucosyl and maltotriosyl derivatives of ß- and ?-cyclodextrin, which may contain one or more sugar residues, e.g. glucosyl or diglucosyl, maltosyl or dimaltosyl, as well as various mixtures thereof, e.g. a mixture of maltosyl and dimaltosyl derivatives; cyclodextrin derivatives comprising anionic functional groups such as sulfobutylether derivatives, sulfonates, phosphates, and the like, such as hydroxypropyl-ß-cyclodextrin, hydroxypropyl-?-cyclodextrin, sulfobutylether-ß-cyclodextrin, and sulfobutylether-?-cyclodextrin, as well as hydroxyethyl-ß-cyclodextrin, hydroxyethyl-?-cyclodextrin, dihydroxypropyl-ß-cyclodextrin, glucosyl-ß-cyclodextrin, diglucosyl-ß-cyclodextrin, maltosyl-ß-cyclodextrin, maltosyl-?-cyclodextrin, maltotriosyl-ß-cyclodextrin, maltotriosyl-?-cyclodextrin and dimaltosyl-ß-cyclodextrin

3. A sterile injectable composition as claimed in claim 2, wherein the cyclodextrin derivative is sulfobutylether-ß-cyclodextrin.

4. The sterile injectable composition comprising
(a) nor-UDCA and
(b) sulfobutylether-ß-cyclodextrin.

5. The sterile injectable composition as claimed in claim 4, wherein nor-UDCA and sulfobutylether-ß-cyclodextrin are present in the amount from about 0.1:1 to about 1:0.1.

6. The sterile injectable composition as claimed in claim 4, wherein the composition comprises of about 1 mg/mL to about 100 mg/mL nor-UDCA.

7. The sterile injectable composition as claimed in claim 4, wherein the composition comprises of about 5 mg/mL to about 300 mg/mL sulfobutylether-ß-cyclodextrin.

8. The sterile injectable composition as claimed in claim 6, wherein the composition comprises of about 15 mg/mL to about 40 mg/mL nor-UDCA.

9. The sterile injectable composition as claimed in claim 7, wherein the composition comprises of about 150 mg/mL to about 250 mg/mL sulfobutylether-ß-cyclodextrin.

10. A sterile injectable composition comprising
(a) about 15 mg/mL to about 40 mg/mL nor-UDCA,
(b) about 150 mg/mL to about 250 mg/mL sulfobutylether-ß-cyclodextrin and
(c) water.